Reversible defect of 123 I-15-(p-iodophenyl)-9-(R,S)-methylpentadecanoic acid indicates residual viability within infarct-related area

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1 ORIGINAL ARTICLE Annals of Nuclear Medicine Vol. 16, No. 3, , 2002 Reversible defect of 123 I-15-(p-iodophenyl)-9-(R,S)-methylpentadecanoic acid indicates residual viability within infarct-related area Akira NAKANO,* Yoshiharu YONEKURA,** Jong-Dae LEE,* Hiromasa SHIMIZU,* Norio TAKAHASHI,*** Motosaburo HORIKOSHI,* Kiyotaka OKURA,* Tatsuro TSUCHIDA*** and Takanori UEDA* *First Department of Internal Medicine, **Biomedical Imaging Research Center and ***Department of Radiology, Fukui Medical University To evaluate the relationship between the reversible defect of 123 I-15-(p-iodophenyl)-9-(R,S)- methylpentadecanoic acid (9MPA) and residual viability within an infarct-related area, we performed resting single photon emission computed tomography (SPECT) with 9MPA and positron emission tomography (PET) with 18 F-deoxyglucose (FDG) and 13 N-ammonia (NH 3 ) in 7 patients with prior myocardial infarction. 9MPA-SPECT was obtained 2 min (early) and 50 min (delayed) after tracer injection. Tomographic images of the left ventricle were divided into 13 segments to correlate the regional uptake of each tracer. Residual viability within an infarct-related segment was confirmed by NH 3 - and FDG-PET. Twenty-six infarct-related segments, confirmed by NH 3 -PET, showed reduced uptake of 9MPA on early images. In these 26 segments, 6 showed reversible defect of 9MPA and 20 showed fixed defect on delayed images. Residual viability was present in all segments exhibiting reversible 9MPA defect and 7 segments (35%) exhibiting fixed defect (p < 0.05). The sensitivity, specificity and accuracy of reversible 9MPA defect for the detection of myocardial viability were 46%, 100%, and 73%, respectively. Myocardial clearance of 9MPA was significantly slower in non-viable segments than in ischemic but viable segments (4.9 ± 5.1% vs ± 5.3%; p < 0.05). These data suggest that a reversible 9MPA defect indicates residual viability within the infarctrelated area. Key words: 123 I-15-(p-iodophenyl)-9-(R,S)-methylpentadecanoic acid, reversible defect, myocardial infarction, myocardial viability INTRODUCTION RADIONUCLIDE IMAGING with fatty acid analogue is a sensitive indicator of metabolic alteration in ischemic myocardium. 123 I-15-(p-iodophenyl)-3-(R,S)-methylpentadecanoic acid (BMIPP, Fig. 1) is now widely used for assessing myocardial fatty acid utilization. 1 BMIPP shows prolonged myocardial retention by introducing methyl-branch into the beta-3 position to inhibit beta-oxidation. A number of reports have described the usefulness Received October 11, 2001, revision accepted January 15, For reprint contact: Akira Nakano, M.D., First Department of Internal Medicine, Fukui Medical University, 23 3 Shimoaizuki, Matsuoka-cho, Fukui , JAPAN. anakano@fmsrsa.fukui-med.ac.jp of imaging with BMIPP for evaluating myocardial ischemia in patients with coronary artery disease. Furthermore, combined BMIPP and myocardial perfusion imaging has been shown to assess myocardial viability, namely reduced uptake of BMIPP relative to perfusion indicates the presence of ischemic (metabolically impaired) but viable myocardium (i.e. stunned or hibernating myocardium). 2,3 Nevertheless, as reduced accumulation of BMIPP is observed not only in ischemic but viable myocardium but also in scar tissue, imaging with BMIPP alone is not sufficient for assessing myocardial viability. 123 I-15-(p-iodophenyl)-9-(R,S)-methylpentadecanoic acid (9MPA, Fig. 1) has been designed to be washed out from myocardium by introducing the methyl-branch into the ninth carbon location of the fatty acid chain to undergo beta-oxidation three times, 4 7 so that its clearance is expected to reflect the beta-oxidation of fatty acids. In Original Article 183

2 fact, a few reports have described how the clearance of 9MPA from myocardium was slower in an ischemic region than in a normal region. 4 6 Chouraqui et al. reported that differential myocardial clearance from normal and ischemic regions results in reversible 9MPA defect. 7 We therefore hypothesized that a reversible 9MPA defect indicates the presence of ischemic but viable myocardium. In this study we performed single photon emission computed tomography (SPECT) with 9MPA and positron emission tomography (PET) with 18 F-deoxyglucose (FDG) in patients with prior myocardial infarction to determine whether the reversible 9MPA defect indicates the presence of residual viability within an infarct-related area. MATERIALS AND METHODS Fig. 1 Chemical structure of BMIPP and 9MPA. Seven patients (4 men, 3 women; 54 to 73 years old, mean age 64 ± 6) with prior myocardial infarction (more than 1 month after onset) were recruited for our study. Patients with overt diabetes were excluded. In all subjects, myocardial SPECT imaging with 9MPA, coronary angiography, biplane left ventriculography, PET with FDG and 13 N-ammonia (NH 3 ) were performed. This study was performed as a part of the phase III clinical trial of 9MPA in Japan and was approved by the institutional review board of Fukui Medical University Hospital. Written informed consent was obtained from all patients. Coronary angiography and biplane left ventriculography were performed within 2 weeks of a 9MPA study. Coronary stenosis was measured by the cross-sectional method and significant stenosis was defined as luminal narrowing > 50% after nitroglycerin administration. On left ventriculography, we calculated the left ventricular ejection fraction (EF) by the area-length method. 9MPA (= 160 MBq) was injected at rest after overnight fasting, followed by SPECT acquisition 2 min (early) and 50 min later (delayed). The images were acquired in continuous rotational motion composed of 90 angular samples framed into 4 intervals with a matrix for a total imaging time of 15 min. The photopeak and main window used for data acquisition in imaging were 160 kev and 26%, respectively. The projection images acquired by means of the main window were first smoothed with a Butterworth filter of order 8, and the cut-off frequency was 0.3 cycles/pixel. Image reconstruction was based on filtered backprojection with a ramp filter. Reconstructed transverse slices covered the left ventricular myocardium. These images were further processed to obtain vertical long axial and short axial slices. All subjects underwent PET with FDG and NH 3 after an overnight fast within 2 weeks of 9MPA-SPECT with a whole-body tomograph (ADVANCE, GE, Milwaukee). Before the emission scan was performed, a 10-min transmission scan was performed with 2 rotating 68 Ge pin sources for attenuation correction. Static PET images were acquired over 10 minutes beginning 10 min after an Fig. 2 Schematic representation of tomographic images. intravenous bolus injection of NH 3 (= 740 MBq). FDG (= 370 MBq) was then injected intravenously, and static images were acquired over 10 minutes beginning 60 min after the injection. 8,9 Reconstructed images of the left ventricle (short axial slices and vertical long axial slices) were created. The reconstructed SPECT and PET images of the left ventricular slice (1 vertical long axial slice and 2 short axial slices) were divided into 13 segments to correlate the regional uptake of each tracer (Fig. 2). The myocardial accumulation of 9MPA was assessed visually by 2 independent observers who were unaware of the patient s data with a 4-point defect score (0; normal, 1; mild reduced, 2; moderate reduced, 3; severe reduced). The reduced tracer accumulation was defined as a 2 or 3 defect score, and normal was defined as 0 or 1. According to the findings of early and delayed 9MPA-SPECT, we defined the changes in tracer accumulation in each segment as follows: normal, normal accumulation of 9MPA is observed in both early and delayed images; reversible defect, reduced accumulation of 9MPA on early images altered normal accumulation in delayed images; fixed defect, reduced accumulation of 9MPA is observed in both early and delayed images. Then a circular region of interest (ROI), 10 mm diameter in size, was placed on each segment, and segmental clearance of 9MPA (washout rate; WR) was calculated by using the mean counts in the ROIs in the following equation: WR (%) = [1 (Cd/Ce 0.5 Te d/13 ) 1/Te d ] 100 Ce and Cd are the mean counts in the ROI on early and 184 Akira Nakano, Yoshiharu Yonekura, Jong-Dae Lee, et al Annals of Nuclear Medicine

3 delayed images, respectively, and Te d is denote time (hours) between early and delayed images. We determined that the physical half life of 123 I is 13 hours. For analysis of NH 3 - and FDG-PET images, the myocardial tissue activity per pixel of both tracers (CT; cpm/ ml) was measured in each 13 segments. Infarct-related segments (IRS) were defined as those showing less than 70% of the maximal NH 3 uptake. 8 The FDG uptake in each segment was quantified as the FDG Uptake Index, a percent dose per unit volume of the myocardium (% dose/ 100 ml) in relation to the total injected dose of FDG, described previously. 8,9 According to our previous report, the upper limit of normal FDG Uptake Index is An increase in the FDG Uptake Index above in infarctrelated segments was classified as ischemic but viable tissue, whereas segments with no increase in FDG uptake were classified as non-viable tissue. All data are presented as the mean value ± SD. The unpaired Student s t test was used to assess differences in mean values between groups. The Fisher exact test was used to compare proportions. A p value < 0.05 was considered significant. Fig. 3 Comparisons of myocardial clearance of 9MPA. *p < 0.05 Table 1 Characteristics of the patients Patient Age Sex IRA (% stenosis) LVEF (%) 1 73 M RCA (78) M LAD (88) F LCx (90) F LAD (38) F LCx (24) M LAD (80) M RCA (63) 47 IRA; infarct-related artery, LVEF; left ventricular ejection fraction, RCA; right coronary artery, LAD; left anterior descending artery, LCx; left circumflex artery Fig. 4 A 65-yr-old female with prior myocardial infarction (patient no. 3). Her left circumflex artery was 90% of luminal narrowing. NH 3 -PET images showed hypoperfusion in the lateral left ventricular segments. Increased FDG uptake was observed within the hypoperfused segments, suggesting the presence of residual viability within infarct-related area. Early 9MPA-SPECT showed reduced accumulation in the lateral left ventricular segments. Reversible defect of 9MPA was observed within the infarct-related segments on delayed images. Original Article 185

4 Table 2 Finding of 9MPA-SPECT and FDG-PET (n = 26) 9MPA reversible defect fixed defect FDG viable 6 7 FDG non-viable 0 13 RESULTS Among the findings of coronary angiography, none showed significant stenosis except in infarct-related arteries. The infarct-related arteries (3 left anterior descending arteries, 2 left circumflex arteries and 2 right coronary arteries) were patent in all 7 patients with residual luminal narrowing of 66 ± 26% (range 24% to 90%). Mean left ventricular EF was 52 ± 9% (range 36% to 62%) (Table 1). Of the 91 segments in 7 subjects screened, 27 segments (30%) showed reduced accumulation of 9MPA on early images. In these 27 segments, 26 (96%) were classified as IRS according to the findings of NH 3 -PET. The mean WR of 9MPA in IRS were significantly lower than in 64 segments exhibiting normal NH 3 accumulation (8.8 ± 5.7% vs ± 3.9%; p < 0.05, Fig. 3). In IRS, reversible defect of 9MPA was observed in 6 (23%, Fig. 4) segments and fixed defect in 20 (77%) segments. FDG-PET showed residual tissue viability in 13 of 26 IRS. Of these 13 segments, reversible 9MPA defect was observed in 6 segments (46%) and fixed defect in 7 segments. In the remaining 13 segments without myocardial viability, all showed fixed 9MPA defect (Table 2). Reversible 9MPA defect was more frequently observed in ischemic but viable segments than in non-viable segments (p < 0.05). The sensitivity, specificity and accuracy of reversible 9MPA defect for the detection of myocardial viability were 46%, 100% and 73%, respectively. Myocardial WR of 9MPA was significantly slower in non-viable segments than in ischemic but viable segments (4.9 ± 5.1% vs ± 5.3%; p < 0.05, Fig. 3). DISCUSSION Accurate and noninvasive assessment of myocardial metabolism has played an important role in understanding the physiological condition of ischemic myocardium. PET with FDG or 11 C-acetate is now reported to allow excellent assessment of myocardial metabolism and viability. In patients with prior myocardial infarction, precise assessment of residual viability within an infarctrelated area by means of PET is useful for determining whether or not coronary revascularization is indicated, 10 but PET is not yet widely available. Therefore, BMIPP- SPECT has been widely used for assessing myocardial fatty acid utilization, 1,2 but, to the best of our knowledge, single isotope imaging with BMIPP is not sufficient for assessing myocardial viability in patients with prior myocardial infarction, because reduced accumulation of BMIPP is observed not only in ischemic but viable myocardium, but also in non-viable tissue. Therefore, dual isotope imaging with BMIPP and perfusion tracer (i.e. 201 Tl) is needed to assess myocardial viability. Many reports have stated that reduced uptake of BMIPP relative to perfusion has predictive value for residual viability within an infarct-related area. 1,2 9MPA, a new methyl-branched fatty acid analogue, is different from BMIPP in introducing methyl-branch into the ninth carbon location of the fatty acid chain to undergo beta-oxidation three times. 4 7 Therefore, clearance of 9MPA is expected to reflect beta-oxidation and myocardial viability. A few reports described how the clearance of 9MPA from ischemic myocardium was significantly slower than those from normal myocardium, and that the decreased 9MPA clearance reflects impairment of fatty acids metabolism. 4 6 In our present study, 26 of 27 (96%) segments showing reduced 9MPA uptake on early images corresponded with IRS according to the findings of NH 3 - PET. Clearance of 9MPA from these segments was significantly slower than from 64 segments with normal NH 3 accumulation (8.8 ± 5.7% vs ± 3.9%; p < 0.05). In these 26 IRS, FDG-PET showed 13 segments as ischemic but viable and 13 segments as non-viable. Clearance of 9MPA from non-viable segments was significantly slower than that from ischemic but viable segments (4.9 ± 5.1% vs ± 5.3%, p < 0.05), so that clearance of 9MPA might reflect myocardial fatty acid metabolism and viability. Similarly, Fujiwara et al. reported that the clearance of 9MPA from non-viable segments was slower than that from viable segments in patients with acute coronary syndrome. 6 Our present results might be consistent with their report, but it is not fully investigated whether the presence of a reversible defect in 9MPA, resulting from different myocardial clearance from ischemic but viable and normal regions, indicates the residual viability within an infarct-related area. Chouraqui et al. reported that 9MPA correlates closely with 201 Tl for initial postexercise myocardial uptake and defect reversibility in patients with exercise-induced myocardial ischemia. 7 They suggested that defect reversibility of 9MPA appears to result from differential myocardial clearance from normal and ischemic regions. In our present study, the reversible defect of 9MPA is frequently observed in patients with prior myocardial infarction and closely related to the presence of residual viability within an infarct-related area. We speculated that the reversible defect of 9MPA is a predictor of preserved fatty acid metabolism within an infarct-related area. Nevertheless, it is likely that slower clearance of 9MPA from non-viable segments than from ischemic but viable segments is a disadvantage for detecting residual viability by using the phenomenon of reversible defect, but normalized % uptake of 9MPA on early images was significantly lower in 186 Akira Nakano, Yoshiharu Yonekura, Jong-Dae Lee, et al Annals of Nuclear Medicine

5 non-viable segments than in ischemic but viable segments (52.3 ± 2.6% vs ± 6.2%, p < 0.05). We speculated that this lower uptake of 9MPA on early images in nonviable segments caused fixed defect on delayed images. As a result, the sensitivity, specificity and accuracy of reversible 9MPA defect for the detection of residual viability were 46%, 100%, and 73%, respectively. In conclusion, 9MPA has unique characteristics different from conventional fatty acid analogues and has important implications for clinical decision making in prior myocardial infarction. ACKNOWLEDGMENT We thank Teruo Matsushita, RT, and Katsuya Sugimoto, RT, for their technical assistance. We also thank the Daiichi Radioisotope Laboratory, Japan for supplying 9MPA. REFERENCES 1. Knapp FF Jr, Kropp J. Iodine-123-labeled fatty acids for myocardial single-photon emission tomography: current status and future perspectives. Eur J Nucl Med 1995; 22: Kawamoto M, Tamaki N, Yonekura Y, Tadamura E, Fujibayashi Y, Magata Y, et al. Combined study with I-123 fatty acid and thallium-201 to assess ischemic myocardium: comparison with thallium redistribution and glucose metabolism. Ann Nucl Med 1994; 8: De Geeter F, Franken PR, Knapp FF Jr, Bossuyt A. Relationship between blood flow and fatty acid metabolism in subacute myocardial infarction: a study by means of 99m Tc- Sestamibi and 123 I-beta-methyl-iodo-phenyl pentadecanoic acid. Eur J Nucl Med 1994; 21: Nakajima K, Taki J, Yamamoto W, Takata S, Shimizu M, Tonami N. Myocardial fatty acid imaging with 123 I-labeled 9-methyl-branched pentadecanoic acid (9MPA) using SPET. Nucl Med Commun 1998; 19: Hashimoto J, Kubo A, Iwasaki R, Fujii H, Kunieda E, Iwanaga S, et al. Scintigraphic evaluation of myocardial ischaemia using a new fatty acid analogue: iodine-123- labeled 15-(p-iodophenyl)-9-(R,S)-methylpentadecanoic acid (9MPA). Eur J Nucl Med 1999; 26: Fujiwara S, Takeishi Y, Tojo T, Yamaoka M, Nitobe J, Takahashi K, et al. Fatty acid imaging with 123 I-15-(piodophenyl)-9-R,S-methylpentadecanoic acid in acute coronary syndrome. J Nucl Med 1999; 40: Chouraqui P, Maddahi J, Henkin R, Karesh SM, Galie E, Berman DS. Comparison of myocardial imaging with iodine-123-iodophenyl-9-methyl pentadecanoic acid and thallium-201-chloride for assessment of patients with exerciseinduced myocardial ischemia. J Nucl Med 1991; 32: Nakano A, Lee J-D, Shimizu H, Tsuchida T, Yonekura Y, Ishii Y, et al. Reciprocal ST-segment depression associated with exercise-induced ST-segment elevation indicates residual viability after myocardial infarction. J Am Coll Cardiol 1999; 33: Nakano A, Lee J-D, Shimizu H, Yonekura Y, Ueda T. Clinical significance of augmented fluorine-18 deoxyglucose uptake in remote normoperfused myocardium in patients with acute coronary syndrome under fasting conditions. J Nucl Cardiol 2000; 7: Tamaki N, Kawamoto M, Tadamura E, Magata Y, Yonekura Y, Nohara R, et al. Prediction of reversible ischemia after revascularization: perfusion and metabolic studies with positron emission tomography. Circulation 1995; 91: Original Article 187